Inability to produce epinephrine is associated with increased risk of hypoglycemia in infants and children, many of whom have a history of severe stress before or around birth. This defect may result from permanent injury to the adrenal medulla occurring at the time of early severe stress. A large surge of circulating epinephrine and norepinephrine normally occurs in most infants at birth, but the physiological function of this event is not clear. Our goal is to determine the importance of epinephrine in metabolic homeostasis immediately after birth and later in childhood. In ongoing clinical studies, we are monitoring the catecholamine surge at birth to identify factors that account for normal variation and determine whether some newborns fail to mount a surge or have an excessive surge. We want to find if such infants have any abnormality of energy metabolism immediately after birth or have subsequent inability to produce epinephrine. Cord artery blood obtained at 125 deliveries, many from high rise mothers, has shown treat variation of catecholamine levels. The variation is related in part to severity of acidosis, consistent with previous evidence. Two small for gestational age infants had extremely high surges, 10-20 fold higher than average. Two other infants had no surge despite severe acidosis, and they became hypoglycemic soon after birth. These and similar infants will be tested with 2- deoxyglucose at age 2-4 yr to determine if these observations are related to persistent inability to produce epinephrine. New studies will be undertaken in animal models of experimental epinephrine deficiency to better understand the mechanism of its metabolic role. It is postulated that epinephrine may be critical in stimulating rapid metabolic changes required for recovery from hypoxemic lactic acidosis. Uterine artery ligation in pregnant rats and guinea pigs will be used to produce fetal adrenal medullary insufficiency. Initially, cyclic AHP-dependent induction of messenger RNA for the gluconeogenic enzyme, phosphoenolpyruvate carboxykinase, will be compared in the presence and absence of endogenous epinephrine in newborn animals. Subsequently, we will examine the effects of epinephrine deficiency on regulation of the activity of key enzymes of glycogenolysis (phosphorylase), lipolysis (hormone sensitive lipase), and glucose oxidation (pyruvate dehydrogenase complex) around birth and in older fasting animals. These clinical and animal studies will provide complementary approaches toward understanding the metabolic roles of epinephrine around birth and during childhood.